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Hi everyone,

We know that inflammation is a key part of the recovery and repair strategy of the CNS, now we have a protein, (TREM-2), which appears to play a vital role in this. Not only does it trigger macrophages, (white blood cells), to engulf and destroy all the dead bits of myelin which are hanging around after damage has occurred, but it then calms down the inflammation which, if it lasts too long, can itself begin to cause damage.
There is a suspicion that a major difference, (perhaps the only one), between relapsing MS and progressive, is that if you have a remission it occurs during this repair period -- in those lucky enough to have a "better" immune response.
I wondered if levels of TREM-2 could account for different types of MS... those with average levels don't get MS at all because the protein triggers the normal amount of repair and maintenance which should be going on all the time; slightly low, and you get some repair but not quite enough to recover from every attack, (RRMS); very low, and the deterioration is almost constant, (PPMS).

The good news is, bone-marrow cells are easy to get hold of, and migrate from the bloodstream during an attack.

Dom.

Public release date: 9-Apr-2007
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Contact: Andrew Hyde
press@plos.org
44-122-346-3330
Public Library of Science

Modified bone marrow cells can help recovery in an animal model of multiple sclerosis
A new study published in PLoS Medicine has shown that modified bone marrow cells can help recovery in an animal model of multiple sclerosis (MS). Harald Neumann and colleagues from the University of Bonn modified myeloid precursor cells to express a protein (triggering receptor expressed on myeloid cells-2 (TREM2), which is normally made by microglia - a cell from the nervous system - and injected these TREM2-expressing cells into the veins of mice with experimental autoimmune encephalomyelitis (EAE, an animal model of MS).

The researchers examined the migration of these cells into the spinal cord of the mice, their effect on the symptoms of EAE, and what effect there was on the clearance of cell debris and inflammatory responses in the spinal cord of the mice. They found that neither TREM2-expressing nor control myeloid precursor cells migrated into the spinal cord when injected into healthy mice or into animals just beginning to show the symptoms of EAE. However, both control and modified cells migrated into the spinal cord when injected into animals when EAE symptoms were at their peak. The injection of TREM2-expressing myeloid precursor cells (but not control myeloid precursor cells) at this time reduced EAE symptoms and nerve damage, and halted loss of myelin and also increased the clearance of cell debris and myelin fragments.

These findings will need to be repeated in further animal models before the implications for human disease are clear; however, they open up an avenue of further research.


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Citation: Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4(4): e124.

PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://medicine.plosjournals.org/perlse ... ed.0040124

PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-04-04-neumann.pdf

Related image for press use: http://www.plos.org/press/plme-04-04-neumann.jpg

- Caption: TREM2-transduced myeloid precursors (green) facilitating tissue debris clearance in an inflammatory spinal cord lesion of experimental autoimmune encephalomyelitis

CONTACT:
Harald Neumann
Institute of Reconstructive Neurobiology/ Uni Bonn
Neural Regeneration
Sigmund-Freud-Str. 25
Bonn, NRW 53127
Germany
+49.228.6885.541
hneuman1@uni-bonn.de

About PLoS Medicine:

PLoS Medicine is an open access, freely available international medical journal. It publishes original research that enhances our understanding of human health and disease, together with commentary and analysis of important global health issues. For more information, visit http://www.plosmedicine.org

About the Public Library of Science:

The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical literature a freely available public resource. For more information, visit http://www.plos.org



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Hi Dom,
Although obviously a lot more needs to be proven, I like your hypothesis and I like the fact that it might align nicely with the effects of the hygiene hypothesis

You know what comes to mind when I read articles like this one? In this particular case I honestly feel that researchers are missing the boat in not testing these same things against a control population in remote areas of Africa or the Amazon where MS is rare.

It might be said that everyone in the developed populations has the primary predisposition to MS and in that light making comparisons of people with MS with "unaffected" controls from the same population is and always has been foolish.

The entire history of MS research has been similar to trying to understand heart disease only comparing the systems of heart attack victims with the systems of people who are minutes away from having a heart attack. Of course it's going to be hard to find vast differences between the two.

The only way to understand heart disease is to compare the system of someone unaffected by heart disease with the system of a person who is affected by heart disease. In keeping, the only way to understand MS is to compare the systems of those without predominant predisposition towards MS with those who have MS.

Too much thinking. Mine head hurts. I must retire.

Bob

Precisely, Bob: you can't know what's "wrong" with something until you know EXACTLY how it should look when it's "right", and perhaps the way to do this is to look at a low risk population and play "spot the difference". It would be horrendously complicated though; you'd have to examine everything right down to the cellular level.

With reference to the article above, I wonder if anyone has ever tested MS patients for expression of TREM-2?

Dom.

Hi Dom,
I don't know if it's favorable or scary but we think eerily alike. When I started writing my last post the intention was to mention that I hadn't yet read the full article but I'd hope the researchers were on the ball enough to have compared the TREM-2 levels between people with MS and people without.....but at about that point I got sidetracked with the mindset that even people who live in the developed countries without MS can't be considered pristine controls.

To be honest, I think it's justified to consider that people with MS have it many years before they have any inkling that anything is out of the ordinary. In some cases, such as those who spend years in "limbo" it could be many years after that before they have a real diagnosis. I think it's justified to consider there are an untold number of people with milder forms of MS who will die of old age without a diagnosis. Is it possible that everyone in the US and UK have MS and it's only diagnosed in the worst cases when obvious problems arise? We've already been told that everyone produces mrtc's and that the systems of people with MS don't keep the numbers of those mrtc's in check. Has anyone checked to see if populations in "undeveloped" countries also produce mrtc's or is that only unique to our population and researchers "assume" that all humans produce mrtc's? Too many loose ends and dropped balls in the history of MS research for me.

Bob

hello Bob,

Yes, it is a bit spooky that we seem to think along the same lines and ask the same questions -- not sure if anyone has the answers yet, though.

I've been doing a bit more research into TREM-2: it seems to work in conjunction with a protein called DAP-12 which is involved with the development of osteoclasts, (cells which continuously break down bone), and oligodendrocytes. Deficiency in this can lead to a rare condition called PLOSL or, (take a deep breath), polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy. One of the surprising things here is that oligodendrocytes were previously thought to originate in the neural epithelial cells and were not myeloid, (originating from the bone marrow), at all, but now it seems that at least some are.
DAP-12 has other receptors which, in the absence of TREM-2 and the presence of inflammatory conditions, promote macrophages, dendritic cells, and microglial cells.
The DAP-12/TREM-2 pathway may also have an influence on actin polymerisation , which is how oligodendrocytes wrap their extensions around axons. When actin polymerisation is inhibited, release of arachidonic acid is enhanced, which is also part of the glutamate excitotoxicity cascade.

Oops, got a bit sidetracked myself, there. Just to say that I have heard of autopsies performed on people who have died of "natural causes", (ie gored by a rhinoceros, hit by a falling piano: that kind of thing), who had "had MS but never knew it". I think this was a long time ago, though, so I'm not sure you can take it as fact: it was probably before CIS was identified, and at a time when the discovery of a lesion was absolute proof that the person had MS,

Dom.
PS I've downloaded those articles, but haven't read them yet: thank you.

TwistedHelix wrote: PS I've downloaded those articles, but haven't read them yet: thank you.

Good, I think you'll find them interesting.
Bob

Hi, Dom

Thanks for these articles.

Kind regards,
Tony

Hi Dom,
Well spoken, just like a researcher. I am proud to admit that I somewhat understood the part where you said something about "hello Bob"

TwistedHelix wrote:hello Bob, it seems to work in conjunction with a protein called DAP-12 which is involved with the development of osteoclasts, (cells which continuously break down bone), and oligodendrocytes. Deficiency in this can lead to a rare condition called PLOSL or, (take a deep breath), polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy. One of the surprising things here is that oligodendrocytes were previously thought to originate in the neural epithelial cells and were not myeloid, (originating from the bone marrow), at all, but now it seems that at least some are.
DAP-12 has other receptors which, in the absence of TREM-2 and the presence of inflammatory conditions, promote macrophages, dendritic cells, and microglial cells.
The DAP-12/TREM-2 pathway may also have an influence on actin polymerisation , which is how oligodendrocytes wrap their extensions around axons. When actin polymerisation is inhibited, release of arachidonic acid is enhanced, which is also part of the glutamate excitotoxicity cascade.Dom.

Sorry, bob, it is a bit convoluted... how about, 'TREM-2 is good';?

dom.

Now THAT I can understand!

Thanks Dom!